Evidence is accumulating that damage and apoptotic death of neurons plays a role in a large number of neurologic disorders, including HIV-associated dementia (HAD), Alzheimer's disease, multiple sclerosis, stroke, and glaucoma. A contributing factor to these diseases is the activation of matrix metalloproteinases (MMPs) in the extracellular matrix. We hypothesize that this leads to a previously unrecognized extracellular signaling pathway contributing to neuronal cell injury and death. However, the mechanism of activation of MMPs in these disease processes, and specifically in HAD, remains a mystery. Here we will study whether nitric oxide (NO)-related molecules, another factor in neurodegeneration in HAD, can trigger the activation of MMPs and thus initiate an extracellular proteolytic cascade contributing to neuronal damage and apoptosis. Specific Aims: 1. To characterize the chemical nature of NO-activation of MMPs (-2 and -9) in vivo in the gp120-transgenic mouse model of HIV-related CNS damage and in human postmortem samples of HAD brain. Hypothesis tested: NO-activation of MMPs occurs via S-nitrosylation followed by further oxidation of the critical thiol group to irreversible sulfinic and sulfonic acid derivatives during HAD. 2. To determine if NO-activation of MMPs leads to laminin degradation and subsequent neuronal cell injury and death in vitro and in vivo. Hypothesis tested: NO generation and subsequent activation of MMPs can contribute to neuronal cell injury and death by an extracellular proteolysis cascade involving, at least in part, laminin degradation. In the future, the work proposed here may lead to new therapeutic targets based on the novel extracellular signaling pathway involving NO-related molecules and the MMPs that will be studied.